metastatic melanoma - new therapies and their toxicities ... · new therapies and their toxicities...
TRANSCRIPT
![Page 1: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/1.jpg)
Metastatic MelanomaNew therapies and their
toxicitiesMelissa Eastgate
Deputy Director Medical OncologyChair, Melanoma MDT RBWH
RBWH21 July 2018
![Page 2: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/2.jpg)
Question 1:
• How many people die in Australia each year from melanoma?a) 300b) 1600c) 10000
![Page 3: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/3.jpg)
Question 2:
• What is the 2 year survival for someone with metastatic melanoma treated with immunotherapy?a) 10%b) 30%c) 55%
![Page 4: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/4.jpg)
Melanoma Incidence in Australia
• 2015– 1675 deaths – 12960 new cases– 3.6% of cancer deaths
![Page 5: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/5.jpg)
AJCC staging – 8th edition
• T1 measured to 1 decimal place not 2• Tumour mitotic rate removed
![Page 6: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/6.jpg)
![Page 7: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/7.jpg)
![Page 8: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/8.jpg)
0 1 2 3 4 5 6 7 8
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Yrs
Prop
ortio
n Su
rviv
ing
9 10 11 1312 14 15
Stage I (n = 9175)
Stage II (n = 5739)
Stage III (n =1 528)
Stage IV (n = 1158)
Survival in Melanoma by Stage
Balch CM, et al. J Clin Oncol. 2001;19:3635-3648.
![Page 9: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/9.jpg)
Melanoma skin cancer incidence and mortality, 1968 to 2012
![Page 10: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/10.jpg)
Where can we make a difference?
• Prevention/early detection• Better neo/adjuvant therapy• Improved treatment in the advanced setting.
– Downstage to enable curative treatment– Picking the right treatment for the right patient– Prolong overall survival
• Reduced toxicity of treatment
![Page 11: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/11.jpg)
Metastatic melanoma available treatment: 1970–2015
<1990 2000 2010 201420122011 2013 2015
Proleukin(high-dose IL-2)
Jan 1998
DTIC-Dome (dacarbazine)
1970s
DTIC-Dome (dacarbazine)
May 1975
Yervoy(ipilimumab)
Jul 2011
Zelboraf(vemurafenib)
Feb 2012
Yervoy(ipilimumab)
Mar 2011Keytruda
(pembrolizumab)
Sep 2014
Zelboraf(vemurafenib)
Aug 2011
Tafinlar/Mekinistmonotherapies
(dabrafenib/trametinib)
May 2013
Tafinlar + Mekinist(dabrafenib + trametinib)
dual therapyJan 2014
Opdivo (nivolumab)
Dec 2014
Tafinlar + Mekinistdual therapy(dabrafenib + trametinib)
Aug 2015Tafinlar
(dabrafenib)
Sept 2013
Keytruda(pembrolizumab)
July 2015
Opdivo (nivolumab)
June 2015
![Page 12: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/12.jpg)
Sentinel Lymph Node biopsy
• Very important prognostic factor• Should be discussed with patients if
melanoma is >1mm thick• Can’t be done after WLE
![Page 13: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/13.jpg)
Surgery for melanoma
• No benefit for completion LN dissection in patients with a positive sentinel node now confirmed in 2 studies
![Page 14: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/14.jpg)
![Page 15: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/15.jpg)
![Page 16: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/16.jpg)
![Page 17: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/17.jpg)
![Page 18: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/18.jpg)
IMMUNOTHERAPY
![Page 19: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/19.jpg)
Drug classes
• Anti CTLA4 antibody – Ipilimumab
• PD1/PDL1 inhibitors– Pembrolizumab– Nivolumab
![Page 20: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/20.jpg)
Pembrolizumab Versus Ipilimumab For Advanced Melanoma: <br />Final Overall Survival Analysis of KEYNOTE-006
Presented By Jacob Schachter at 2016 ASCO Annual Meeting
![Page 21: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/21.jpg)
Overall Survival
Presented By Jacob Schachter at 2016 ASCO Annual Meeting
![Page 22: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/22.jpg)
Updated Results From a Phase III Trial of Nivolumab Combined With Ipilimumab in Treatment-naïve Patients With Advanced Melanoma (Checkmate 067)
Presented By Jedd Wolchok at 2016 ASCO Annual Meeting
![Page 23: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/23.jpg)
Progression-Free Survival (Intent-to-Treat Population)
Presented By Jedd Wolchok at 2016 ASCO Annual Meeting
![Page 24: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/24.jpg)
Adjuvant Therapy With Nivolumab Versus Ipilimumab After Complete Resection of Stage III/IV
Melanoma: Updated Results from a Phase 3 Trial (CheckMate 238)
Jeffrey Weber,1 Mario Mandala,2 Michele Del Vecchio,3 Helen Gogas,4 Ana M. Arance,5C. Lance Cowey,6 Stéphane Dalle,7 Michael Schenker,8 Vanna Chiarion-Sileni,9 Ivan Marquez-Rodas,10
Jean-Jacques Grob,11 Marcus Butler,12 Mark R. Middleton,13 Michele Maio,14 Victoria Atkinson,15
Reinhard Dummer,16 Veerle de Pril,17 Anila Qureshi,17 Abdel Saci,17 James Larkin,18* Paolo A. Ascierto19*
1NYU Perlmutter Cancer Center, New York, New York, USA; 2Papa Giovanni XIII Hospital, Bergamo, Italy; 3Medical Oncology, National Cancer Institute, Milan, Italy; 4University of Athens, Athens, Greece; 5Hospital Clínic de Barcelona, Barcelona, Spain; 6Texas Oncology-Baylor Charles A. Sammons Cancer Center, Dallas, Texas, USA; 7Hospices Civils de Lyon, Pierre Bénite, France; 8Oncology Center Sf Nectarie Ltd., Craiova, Romania; 9Oncology Institute of Veneto IRCCS, Padua, Italy; 10General University Hospital Gregorio Marañón, Madrid, Spain; 11Hôpital de la Timone, Marseille, France; 12Princess Margaret Cancer Centre, Toronto, Ontario, Canada; 13Churchill Hospital, Oxford, United Kingdom; 14Center for Immuno-Oncology, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy; 15Gallipoli Medical Research Foundation and University of Queensland,
Brisbane, Australia; 16University Hospital Zurich, Switzerland; 17Bristol-Myers Squibb, Princeton, New Jersey, USA; 18Royal Marsden NHS Foundation Trust, London, UK; 19Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy; *Contributed equally to this study.
Abstract Number 9502
![Page 25: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/25.jpg)
CheckMate 238: 24-Month Follow-Up
CA209-067: Study Design CheckMate 238: Study Design
Patients with:• High-risk, completely
resected stage IIIB/IIIC or stage IV (AJCC 7th
edition) melanoma• No prior systemic
therapy• ECOG 0-1
Enrollment period: March 30, 2015 to November 30, 2015
Follow-up
Maximum treatment
duration of 1 year
NIVO 3 mg/kg IV Q2W and
IPI placebo IV Q3W for 4 doses
then Q12W from week 24
IPI 10 mg/kg IV Q3W for 4 doses
then Q12W from week 24 and
NIVO placebo IV Q2W
1:1
n = 453
n = 453
Stratified by: 1) Disease stage: IIIB/C vs IV M1a-M1b vs IV M1c2) PD-L1 status at a 5% cutoff in tumor cells
![Page 26: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/26.jpg)
CheckMate 238: 24-Month Follow-Up
Primary Endpoint: RFS in All PatientsR
FS (%
)
Months
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 24 273 9 15 21 30 33
NIVOIPI
Number of patients at risk
NIVOIPI
NIVO IPIEvents/patients 171/453 221/453Median (95% CI) 30.8 (30.8, NR)a 24.1 (16.6, NR)HR (95% CI) 0.66 (0.54, 0.81)Log-rank P value <0.0001
63%
50%
70%
60%
453 353 311 280 205 28394 331 291 264 7 0453 314 251 216 149 23363 270 230 204 5 0
66%
53%
aMedian estimate not reliable or stable due to few patients at risk.
![Page 27: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/27.jpg)
CheckMate 238: 24-Month Follow-Up
Stage III Stage IVNIVO IPI
Events/patients 135/368 174/366
Median (95% CI) NR 25.5 (16.6, NR)
HR (95% CI) 0.68 (0.54, 0.85)
NIVO IPI
Events/patients 35/82 47/87
Median (95% CI) 30.8 (15.9, NR)a 15.4 (8.5, NR)
HR (95% CI) 0.68 (0.44, 1.06)
Subgroup Analysis of RFS: Disease Stage III and IV
NIVOIPI
RFS
(%)
Months
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 27 333 9 15 21 3024
368 291 258 230 22 0320 272 240 217NIVO 4166366 259 207 179 18 0298 223 190 169IPI 3121
Number of patients at risk
72%
61%
64%
52%
NIVOIPI
RFS
(%)
Months
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 27 333 9 15 21 3024
82 59 51 48 6 071 56 49 45NIVO 33787 55 44 37 5 065 47 40 35IPI 228
Number of patients at risk
63%
56%
58%
44%
67%
55%
61%
47%
aMedian estimate not reliable or stable due to few patients at risk.
![Page 28: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/28.jpg)
CheckMate 238: 24-Month Follow-Up
BRAF Mutant BRAF Wild typeNIVO IPI
Events/patients 73/187 95/194
Median (95% CI) 30.8 (30.8, NR)a 24.6 (14.8, NR)
HR (95% CI) 0.73 (0.54, 0.99)
NIVO IPI
Events/patients 73/197 107/212
Median (95% CI) NR 16.6 (11.4, NR)
HR (95% CI) 0.61 (0.45, 0.82)
NIVOIPI
RFS
(%)
Months
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 27 333 9 15 21 3024
187 142 126 117 16 0157 135 120 110NIVO 483194 142 112 96 11 0155 118 103 91IPI 267
Number of patients at risk
68%
62%
62%
52%
NIVOIPI
RFS
(%)
Months
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 27 333 9 15 21 3024
197 154 137 121 11 0172 144 127 115NIVO 291212 138 109 91 9 0171 121 97 85IPI 362
Number of patients at risk
72%
56%
64%
46%
65%
54%
66%
49%
aMedian estimate not reliable or stable due to few patients at risk.
Subgroup Analysis of RFS: BRAF Mutation Status
![Page 29: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/29.jpg)
If not vigilant, may result in more serious immune-related AEs
Pulmonary Pneumonitis Interstitial lung
disease Acute interstitial
pneumonitis
Neurologic Autoimmune neuropathy Demyelinating
Polyneuropathy Guillain-Barre Myasthenia gravis–like
syndrome
Hepatic Hepatitis,
autoimmune
Gastrointestinal Colitis Enterocolitis Necrotizing colitis GI perforation
Endocrine Hypothyroidism Hyperthyroidism Adrenal
insufficiency Hypophysitis
Eye Uveitis Iritis
Renal Nephritis,
autoimmune Renal failure
Skin Dermatitis exfoliative Erythema multiforme Stevens-Johnson syndrome Toxic epidermal necrolysis Vitiligo Alopecia
Immune-Related AEs With Immunotherapy
Slide credit: clinicaloptions.com
![Page 30: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/30.jpg)
Weber JS, et al. J Clin Oncol. 2012;30:2691-2697.
Kinetics of Appearance of irAEs With Ipilimumab
Rash, pruritusLiver toxicityDiarrhea, colitisHypophysitis
Toxi
city
Gra
de
Wks140 2 4 6 8 10 12
Combined analysis of 325 participants with 10 mg/kg IV q3w x 4
Slide credit: clinicaloptions.com
![Page 31: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/31.jpg)
Immune-Mediated Endocrinopathies
• Can be serious or fatal if not managed correctly
• Hypophysitis, thyroid disease, and primary adrenal insufficiency have all been reported
• Mechanism of injury not fully understood
• Monitor pt for pituitary, thyroid, or adrenal disease
• Check TFTs at baseline and prior to each dose
• Time to onset may be much later; median 11 wks
Corsello SM, et al. J Clin Endocrinol Metab. 2013;98:1361-1375.
Pituitary gland
Hypothalamus
Thyroid gland
T4 T3
SULTsUGTs
liver
01
T4→T3
T3/TR
rT3,T2inactive
T4/T3-sulfateT4/T3-glucuronide inactive
Excretion
T4 >> T3
02.03
Slide credit: clinicaloptions.com
![Page 32: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/32.jpg)
TARGETED THERAPY
![Page 33: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/33.jpg)
BRIM-3: OS with vemurafenib vs DTIC in patients with BRAF V600E-mutant melanoma
OS=overall survival; CI=confidence interval; HR=hazard ratio. McArthur GA, et al. Lancet Oncol 2014;15:323–32.
Vemurafenib(n=295)
DTIC(n=303)
Median OS, months (95% CI) 13.3 (11.9–14.9) 10.0 (8.0–14.0)
Adjusted HR (95% CI) 0.75 (0.60–0.93)
Ove
rall
surv
ival
(%)
100
0
80
60
40
20
01 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
295 294 293 285 274 261 244 223 212 198 181 172 153 138 121 95 75 58 37 25 15 7 3 1 1303 275 251 220 196 175 157 142 118 103 90 84 73 68 59 46 32 27 23 13 7 4 0 0 0
VemurafenibDacarbazine
VemurafenibDacarbazine
HR 0.75 (95% Cl 0·60–0·93)p=0.0085
Time from randomisation (months)Number at risk
![Page 34: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/34.jpg)
Genomic Analysis and 3-Year Efficacy and Safety Update of COMBI-d<br />A phase 3 study of dabrafenib + trametinib vs dabrafenib monotherapy in patients with unresectable or metastatic BRAF V600E/K–mutant cutaneous melanoma
Presented By Keith Flaherty at 2016 ASCO Annual Meeting
![Page 35: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/35.jpg)
COMBI-d: PFS and OSa
Presented By Keith Flaherty at 2016 ASCO Annual Meeting
![Page 36: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/36.jpg)
COMBI-d: Normal LDHa and < 3 Disease Sitesb
Presented By Keith Flaherty at 2016 ASCO Annual Meeting
![Page 37: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/37.jpg)
Pyrexia managment
• Mild – paracetamol, NSAIDs• Moderate or associated with rigors,
dehydration – withhold dabrafenib/trametinibuntil resolves
• Severe, involving hypotension, renal failure –withhold dabrafenib/trametinibsteroidsonce resolved can safely restart therapy
![Page 38: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/38.jpg)
Australian context
Stage 3/resected stage 4• Adjuvant therapy currently under consideration by PBAC
Stage 4• BRAF mutant – dabrafenib/trametinib or
vemurafenib/cobimetinib on PBS
• BRAF wildtype – pembrolizumab/nivolumab on PBS – Compassionate access to Ipi/nivo combination
![Page 39: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/39.jpg)
Australian context
• Ongoing trials – PD1 +CTLA4SequencingCombination braf/immunotherapyImmunotherapy plus other agents
![Page 40: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/40.jpg)
Case
• 63 year old male• Melanoma removed from shoulder 2013• March 2015 presented with R arm weakness
then seizures• Imaging showed multiple brain mets as well as
lung and mediastinal disease• Bronchoscopy and biopsy confirmed
metastatic melanoma• BRAF wild type
![Page 41: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/41.jpg)
![Page 42: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/42.jpg)
![Page 43: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/43.jpg)
![Page 44: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/44.jpg)
Case 1 cont’d
• Seizures controlled on dex/carbamazepine• Started on pembrolizumab early May 2015• Early June phone call from family – R arm
weakness had worsened, some confusion• Dexamethasone increased to 4mg bd• Pembrolizumab continued• July - arm weakness better, no seizures, dex
reduced to 2mg daily then subsequently ceased
![Page 45: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/45.jpg)
Case 1 cont’d
• Now:– Working in son’s business– No seizures– Back driving– Near complete response on scans
• PET no disease• MRI not quite normal
– Toxicity: mild diarrhea– Treatment ceased
![Page 46: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/46.jpg)
![Page 47: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/47.jpg)
![Page 48: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/48.jpg)
![Page 49: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/49.jpg)
![Page 50: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/50.jpg)
![Page 51: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/51.jpg)
![Page 52: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/52.jpg)
Autoimmune hepatitis
![Page 53: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/53.jpg)
Other toxicities – rash D/T
![Page 54: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/54.jpg)
Other toxicities – rash pembro
![Page 55: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/55.jpg)
Question 1:
• How many people die in Australia each year from melanoma?a) 300b) 1600c) 10000
![Page 56: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/56.jpg)
Answer
• 1600
![Page 57: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/57.jpg)
Question 2:
• What is the 2 year survival for someone with metastatic melanoma treated with immunotherapy?a) 10%b) 30%c) 55%
![Page 58: Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities Melissa Eastgate Deputy Director Medical Oncology. Chair, Melanoma MDT RBWH. RBWH](https://reader033.vdocument.in/reader033/viewer/2022042311/5ed8ec5a6714ca7f4768d28f/html5/thumbnails/58.jpg)
Answer
• 55%